Zosuquidar trihydrochloride

SKU: orb1301147

Description

Zosuquidar trihydrochloride (LY-335979 trihydrochloride) is a potent, third-generation P-glycoprotein (P-gp) inhibitor with a Ki of 60 nM, developed to reverse multidrug resistance in cancer. It has been widely used in both in vitro and in vivo research to investigate chemosensitization and the pharmacokinetic enhancement of co-administered anticancer agents.

Research Area

Neuroscience, Pharmacology & Drug Discovery

Key Properties

• CAS Number: 167465-36-3
• MW: 636.99
• Purity: 100.00% (May vary between batches)
• Formula: C₃₂H₃₁F₂N₃O₂·3HCl
• SMILES: Cl.Cl.Cl.OC(COc1cccc2ncccc12)CN1CCN(CC1)C1c2ccccc2C2C(c3ccccc13)C2(F)F
• Target: P-gp
• Solubility: DMSO:80.83 mg/mL (126.89 mM)

Bioactivity

• Target IC50:
  SW620 cells:0.059 μM|MDR:6 μM-16 μM|P-gp:60 nM (Ki)
• In Vivo:
  Zosuquidar trihydrochloride is only moderately active as an inhibitor of P-gp at the blood-brain. Zosuquidar trihydrochloride at an oral dose of 25 mg/kg increases the brain concentrations by about 2.5-fold at 1 h and 5-fold at 24 h after paclitaxel administrationbarrier. Zosuquidar enhances the brain uptake of nelfinavir in a dose-dependent manner. Brain tissue/plasma nelfinavir concentration ratios increase from 0.06±0.03 in the absence of zosuquidar administration and 0.09±0.02 between 2 and 6 h after a 2 mg/kg intravenous dose of zosuquidar to 0.85±0.19 after 6h and 1.58±0.67 after 20 mg/kg zosuquidar.
  Read more...
• In Vitro:
  Zosuquidar competitively inhibits equilibrium binding of [3H]vinblastine to Pgp by blocking [3H]azidopine photoaffinity labeling of the Pgp in CEM/VLB100 plasma membranes. Zosuquidar alone shows the cytotoxicity to drug-sensitive and MDR cell lines with IC50 ranging from 6 μM-16 μM and produces its ability to completely reverse the resistance of the oncolytics (vinblastine, doxorubicin, or etoposide) to the MDR cell lines P388/ADR, MCF7/ADR, 2780AD, or UCLA-P3.003VLB at concentration of 0.1 and 0.5 μM. Zosuquidar significantly restores drug sensitivity in P-gp-expressing leukemia cell lines including K562/HHT40, K562/HHT90, K562/DOX and HL60/DNR, and enhances the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. A latest paper indicates that Zosuquidar completely inhibits apically directed transport of (Z)-endoxifen in the ABCB1-transduced cells.
  Read more...
• Cell Research:
  Cell viability is determined using a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction method. Cells are harvested during logarithmic growth phase, and seeded in 96-well plates. The cells are then cultured for 72 hours in the presence of oncolytics with or without modulators. MCF-7 and MCF-7/ADR cells are incubated 24 hours before the addition of the drug with and without the LY335979. LY335979 is prepared as 2 mM DMSO stocks and added to wells to give final concentrations ranging from 0.05 to 5 μM. After 72 hours, 20 μL of freshly prepared 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (5 mg/mL in Dulbecco's PBS) is added to each well and incubated for 4 hours in a 37 °C incubator containing 5% CO2. Cells are pelleted in a Sorvall RT6000B centrifuge, 70 μL of medium is carefully removed from each well, and 100 μL of 2-propanol/0.04 N HC1 is added. Cells are resuspended 5-10 times with a Multipipettor or until no particulate matter is visible. Plates are immediately read on a Titertek Multiskan MCC/340 microplate reader Flow Laboratories with a test wavelength of 570 nm and a reference wavelength of 630 nm. Controls are measured in quadruplicate and modulators are measured in duplicate. Cytotoxicity analyses are also performed using the CeliTiter 96 AQueous assay kit.(Only for Reference)
  Read more...

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

2780, 2780AD, ABCB1, acute myelogenous leukemia, AML, anti-tumor activity, CCRF-CEM, Cluster of differentiation 243, CD243, CEM/VLB100, Inhibitor, HL60, MCF7/ADR, MCF7, MDR1, LY335979, LY-335979, LY335979 Trihydrochloride, LY-335979 Trihydrochloride, LY-335979 trihydrochloride, LY 335979, LY 335979 Trihydrochloride, K562, inhibit, Multidrug resistance protein 1, UCLA-P3, UCLA-P3.003VLB, Zosuquidar, Zosuquidar (LY335979), Zosuquidar (LY335979) 3HCl, Zosuquidar 3HCl, Zosuquidar Trihydrochloride, Zosuquidar trihydrochloride, RS 33295-198, RS 33295-198 (D06387), RS 33295-198 (D06387) 3HCl, RS 33295-198 trihydrochloride, RS 33295-198 Trihydrochloride, P388, P388/ADR, P-gp (P-glycoprotein), Pgp, P-gp, P-glycoprotein

Compound Identifiers

PubChem CID

21865974